Using Epstein-Barr virus, we have established lymphocyte cell lines from peripheral blood of normal subjects and patients with genetic syndromes associated with extreme insulin resistance (i.e., lipoatrophic diabetes, leprechaunism, type A extreme insulin resistance, and Rabson-Mendenhall syndrome). Three biochemical defects have been identified: (1) those with a decreased number of normal insulin receptors; (2) those with a normal number of qualitatively abnormal insulin receptors; and (3) those with a normal number of receptors without any detectable abnormality in insulin binding. Patients with a decrease in the number of insulin receptors on the cell surface results from a decrease in the rate of receptor biosynthesis. The rate of receptor turnover appears to be normal. In cells from one patient with leprechaunism, we have identified several qualitative abnormalities in the insulin receptors: (1) decreased sensitivity to changes in pH and temperature, (2) abnormally high binding affinity for insulin, and (3) defects in positive cooperativity. Based on preliminary studies of the parents' insulin receptors, we have tentatively concluded that the patient is a mixed heterozygote, having inherited two different abnormal alleles from the two parents.